Chronic rhinosinusitis with polyps (CRSwNP) is a significant health problem in the United States. This disorder, which is often particularly recalcitrant to medical and surgical therapy, is characterized by persistent eosinophilic inflammation of the sinonasal mucosa, with thickened secretions that are frequently colonized with bacteria and/or fungi. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. The epithelium of nose and sinuses participates actively in host immunity, serving as a barrier and first line of defense against inhaled pathogens and other potential threats. During the past funding period, we investigated how sinonasal epithelial cells (SNEC) contribute to CRSwNP through production of innate pro-eosinophilic mediators and by bidirectional communication with the adaptive immune system. Our studies using human tissue and mouse models have suggested that SNEC are triggered by epithelial damage to produce mediators that promote eosinophilic inflammation. We hypothesize that this pathway is a normal aspect of healing and repair, but is suppressed by signals associated with microbial infection. To test these hypotheses, we will initially, in aim 1, examine sinus mucosa from patients with acute and chronic sinus inflammatory disease to define the pattern of pro-eosinophilic mediator expression during the resolution phase after intervention. We will also explore in vitro the interplay of damage-associated molecules, microbial molecular patterns, and Th1 cytokines in determining SNEC pro-eosinophilic gene expression. In aim 2, we will utilize mouse models of sinonasal eosinophilic inflammation in combination with knockout mice that lack antimicrobial immunity-associated genes. As part of this aim, the first transgenic animal model of chronic rhinosinusitis will be generated, with great potential to further a wide range of future CRSwNP research. Finally, in aim 3, we will dissect subcellular pathways that regulate abnormal pro-eosinophilic mediator expression in SNEC derived from CRSwNP patients. These studies will significantly advance current knowledge about CRSwNP and create an opportunity to develop innovative therapies for this debilitating and costly medical condition.